Probing the Parliament of Neurons

SEATTLE — When Clay Reid decided to leave his job as a professor at Harvard Medical School to become a senior investigator at the Allen Institute for Brain Science in Seattle in 2012, some of his colleagues congratulated him warmly and understood right away why he was making the move.

Others shook their heads. He was, after all, leaving one of the world’s great universities to go to the academic equivalent of an Internet start-up, albeit an extremely well- financed, very ambitious one, created in 2003 by Paul Allen, a founder of Microsoft.

Still, “it wasn’t a remotely hard decision,” Dr. Reid said. He wanted to mount an all-out investigation of a part of the mouse brain. And although he was happy at Harvard, the Allen Institute offered not only great colleagues and deep pockets, but also an approach to science different from the classic university environment. The institute was already mapping the mouse brain in fantastic detail, and specialized in the large-scale accumulation of information in atlases and databases available to all of science.

Now, it was expanding, and trying to merge its semi-industrial approach to data gathering with more traditional science driven by individual investigators, by hiring scientists like Christof Koch from the California Institute of Technology as chief scientific officer in 2011 and Dr. Reid. As a senior investigator, he would lead a group of about 100, and work with scientists, engineers and technicians in other groups.

Without the need to apply regularly for federal grants, Dr. Reid could concentrate on one piece of the puzzle of how the brain works. He would try to decode the workings of one part of the mouse brain, the million neurons in the visual cortex, from, as he puts it, “molecules to behavior.”

There are many ways to map the brain and many kinds of brains to map. Although the ultimate goal of most neuroscience is understanding how human brains work, many kinds of research can’t be done on human beings, and the brains of mice and even flies share common processes with human brains.

The work of Dr. Reid, and scientists at Allen and elsewhere who share his approach, is part of a surge of activity in brain research as scientists try to build the tools and knowledge to explain — as well as can ever be explained — how brains and minds work. Besides the Obama administration’s $100 million Brain Initiative and the European Union’s $1 billion, decade-long Human Brain Project, there are numerous private and public research efforts in the United States and abroad, some focusing on the human brain, others like Dr. Reid’s focusing on nonhumans.

While the Human Connectome Project, which is spread among several institutions, aims for an overall picture of the associations among parts of the human brain, other scientific teams have set their sights on drilling to deeper levels. For instance, the Connectome Project at Harvard is pursuing a structural map of the mouse brain at a level of magnification that shows packets of neurochemicals at the tips of brain cells.

Photo

When neurons in the brain of a live mouse, top, are active, they flash brightly. Dr. Clay Reid, above left, and colleagues at the Allen Institute for Brain Science are working with mice to better understand the human mind. Above center, areas of the mouse cortex related to vision, and connected to other parts involving visual perception.Credit
Zach Wise for The New York Times

At Janelia Farm, the Virginia research campus of the Howard Hughes Medical Institute, researchers are aiming for an understanding of the complete fly brain — a map of sorts, if a map can be taken to its imaginable limits, including structure, chemistry, genetics and activity.

All these efforts start with maps and enrich them. If Dr. Reid is successful, he and his colleagues will add what you might call the code of a brain process, the language the neurons use to store, transmit and process information for this function.

Not that this would be any kind of final answer. In neuroscience, perhaps more than in most other disciplines, every discovery leads to new questions.

Dr. Reid, 53, grew up in Boston, in a family with deep roots in medicine. His grandfather taught physiology at Harvard Medical School. “My parents were both psychoanalysts,” he said during an interview last fall, smiling as he imagined a headline for this article, “Psychoanalyst’s Kid Probes Brain!”

“I pretty much always knew that I wanted to be a scientist,” he said.

As an undergraduate at Yale, he majored in physics and philosophy and in mathematics, but in the end decided he didn’t want to be a physicist. Biology was attractive, but he was worried enough about his mathematical bent to talk to one of his philosophy professors about concerns that biology would too fuzzy for him.

The professor had some advice. “You really should read Hubel and Wiesel,” he said, referring to David Hubel and Torsten Wiesel, who had just won the Nobel Prize in 1981 for their work showing how binocular vision develops in the brain.

He read their work, and when he graduated in 1982, he was convinced that the study of the brain was both hard science and a wide-open field. He went on to an M.D.-Ph.D. program at Cornell Medical College and Rockefeller University, where Dr. Wiesel had his lab (he would go on to be president of Rockefeller).

As his studies progressed, Dr. Reid began to have second thoughts about pursuing medicine rather than research. Just a week before he was to commit to a neurology residency, he said, “I ran into a friend from the Wiesel lab and said, ‘Save me.’ ”

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A diamond-tipped slicer is used to prepare a piece of a mouse’s brain for examination with a modified electron microscope at the Allen Institute.Credit
Zach Wise for The New York Times

That plea led to postdoctoral research in the Rockefeller lab. He stayed as a faculty member until moving to Harvard in 1996.

Mathematics and physics were becoming increasingly important in neurobiology, a trend that has continued, but there was still a certain tension between different mind-sets, he recalled. He found that there were intangible skills involved in biological research. “Good biological intuition was equally important to chops in math and physics,” he said.

“Torsten once said to me, ‘You know, Clay, science is not an intelligence test.’ ”

Though he didn’t recall that specific comment, Dr. Wiesel said recently that it sounded like something he would have said. “I think there are a lot of smart people who never make it in science. Why is it? What is it that is required in addition?”

Intuition is important, he said, “knowing what kind of questions to ask.” And, he said, “the other thing is a passion for getting to the core of the problem.”

Dr. Reid, he said, was not only smart and full of energy, but also “interested in asking questions that I think can get to the core of a problem.”

At Harvard, Dr. Reid worked on the Connectome Project to map the connections between neurons in the mouse brain. The Connectome Project aims at a detailed map, a wiring diagram at a level fantastically more detailed than the work being done to map the human brain with M.R.I. machines. But electron microscopes produce a static picture from tiny slices of preserved brain.

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Dr. Reid began working on tying function to mapping. He and one of his graduate students, Davi Bock, now at Janelia Farm, linked studies of active mouse brains to the detailed structural images produced by electron microscopes.

Dr. Bock said he recalled Dr. Reid as having developed exactly the kind of intuition and “good lab hands” that Dr. Wiesel seemed to be encouraging. He and another graduate student were stumped by a technical problem involving a new technique for studying living brains, and Dr. Reid came by.

“Clay got on this bench piled up with components,” Dr. Bock said. “He started plugging and unplugging different power cables. We just stood there watching him, and I was sure he was going to scramble everything.” But he didn’t. Whatever he did worked.

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That was part of the fun of working in the lab, Dr. Bock said, “not that he got it right every time.” But his appreciation for Dr. Reid as a leader and mentor went beyond admiration for his “mad scientist lab hands.”

“He has a deep gut level enthusiasm for what’s beautiful and what’s profound in neuroscience, and he’s kind of relentless,” Dr. Bock said.

Showing a Mouse a Picture

That instinct, enthusiasm and relentlessness will be necessary for his current pursuit. To crack the code of the brain, Dr. Reid said, two fundamental problems must be solved.

The first is: “How does the machine work, starting with its building blocks, cell types, going through their physiology and anatomy,” he said. That means knowing all the different types of neurons in the mouse visual cortex and their function — information that science doesn’t have yet.

It also means knowing what code is used to pass on information. When a mouse sees a picture, how is that picture encoded and passed from neuron to neuron? That is called neural computation.

“The other highly related problem is: How does that neural computation create behavior?” he said. How does the mouse brain decide on action based on that input?

He imagined the kind of experiment that would get at these deep questions. A mouse might be trained to participate in an experiment now done with primates in which an animal looks at an image. Later, seeing several different images in sequence, the animal presses a lever when the original one appears. Seeing the image, remembering it, recognizing it and pressing the lever might take as long as two seconds and involve activity in several parts of the brain.

Understanding those two seconds, Dr. Reid said, would mean knowing “literally what photons hit the retina, what information does the retina send to the thalamus and the cortex, what computations do the neurons in the cortex do and how do they do it, how does that level of processing get sent up to a memory center and hold the trace of that picture over one or two seconds.”

Then, when the same picture is seen a second time, “the hard part happens,” he said. “How does the decision get made to say, ‘That’s the one’?”

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Nuno da Costa of the Allen Institute prepared a slice of mouse brain for the modified electron microscope at Dr. Reid’s lab in Seattle. “With the brain, you can always go deeper,” Dr. Reid said.Credit
Zach Wise for The New York Times

In pursuit of this level of understanding, Dr. Reid and others are gathering chemical, electrical, genetic and other information about what the structure of that part of the mouse brain is and what activity is going on.

They will develop electron micrographs that show every neuron and every connection in that part of a mouse brain. That is done on dead tissue. Then they will use several techniques to see what goes on in that part of the brain when a living animal reacts to different situations. “We can record the activity of every single cell in a volume of cortex, and capture the connections,” he said.

With chemicals added to the brain, the most advanced light microscopes can capture movies of neurons firing. Electrodes can record the electrical impulses. And mathematical analysis of all that may decipher the code in which information is moved around that part of the brain.

Dr. Reid says solving the first part of the problem — receiving and analyzing sensory information — might be done in 10 years. An engineer’s precise understanding of everything from photons to action could be more on the order of 20 to 30 years away, and not reachable through the work of the Allen Institute alone. But, he wrote in an email, “the large-scale, coordinated efforts at the institute will get us there faster.” He is studying only one part of one animal’s brain, but, he said, the cortex — the part of the mammalian brain where all this calculation goes on — is something of a general purpose computer. So the rules for one process could explain other processes, like hearing. And the rules for decision-making could apply to many more complicated situations in more complicated brains. Perhaps the mouse visual cortex can be a kind of Rosetta stone for the brain’s code.

All research is a gamble, of course, and the Allen Institute’s collaborative approach, while gaining popularity in neuroscience, is not universally popular. Dr. Wiesel said it was “an important approach” that would “provide a lot of useful information.” But, he added, “it won’t necessarily create breakthroughs in our understanding of how the brain works.”

“I think the main advances are going to be made by individual scientists working in small groups,” he said.

Of course, in courting and absorbing researchers like Dr. Reid, the Allen Institute has been moving away from its broad data-gathering approach toward more focused work by individual investigators.

Dr. Bock, his former student, said his experience suggested that Dr. Reid had not only a passion and intensity for research, but a good eye for where science is headed as well.

“That’s what Clay does,” he said. “He is really good in that Wayne Gretzky way of skating to where the puck will be.”

The Map Makers: Second in a series of articles about scientists behind
the new efforts to explore the brain.

A version of this article appears in print on February 25, 2014, on Page D1 of the New York edition with the headline: The Brain’s Inner Language. Order Reprints|Today's Paper|Subscribe